Study Links Actin Mutations to Development of Heart Disease

It is one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans. Actin is the monomeric subunit of two types of filaments in cells: microfilaments, one of the three major components of the cytoskeleton, and thin filaments, part of the contractile apparatus in muscle cells. Thus, actin participates in many important cellular processes, including muscle contraction, cell motility, cell division and cytokinesis, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape.

To understand the roles that the actin protein plays in the development of heart failure, investigators at the University of Guelph (Canada) pursued a systematic approach toward characterizing human cardiac actin mutants that had been associated with either hypertrophic or dilated cardiomyopathy. Seven known cardiac actin mutants were expressed in a viral growth system, and the intrinsic properties of the actin molecules were studied.

Results published in the May 8, 2012, online edition of the journal PLoS ONE revealed that the changes to the properties of the actin proteins themselves were quite subtle. Substitution of methionine for leucine at amino acid 305 showed no impact on the stability, nucleotide release rates, or DNase-I inhibition ability of the actin monomer. However, during polymerization, a two-fold increase in inorganic phosphate release was observed. The locations of mutations on the actin protein correlated with the molecular effects. In general, mutations in subdomain 3 of the protein affected its stability or affected the polymerization of actin filaments, while mutations in subdomains 1 and 4 more likely affected protein-protein interactions.

“In order to cure heart disease, you have to understand its fundamental properties,” said senior author Dr. John Dawson, professor of molecular and cellular biology at the University of Guelph. “So we looked at variants of naturally occurring proteins that are found in people with heart disease. Heart disease has many different forms and variants. If we can design specific therapies that address the precise mechanisms of the things going on — treat the root cause rather than the whole system — then we can improve the quality of life for people.”

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University of Guelph